Upwards of 33-50% of cancer patients who smoked prior to diagnosis continue to smoke following diagnosis and treatment. Continued smoking by cancer patients reduces survival time, medical treatment efficacy, and quality of life (QOL). To date, studies of smoking cessation interventions for cancer patients have failed to yield significant treatment effects. As such, currently, there is no evidence-based treatment model for addressing tobacco use in this population. With medical advances in cancer care yielding a growing constituency of cancer survivors - close to 12 million today - addressing nicotine dependence in this population is a priority. A recent NCI meeting called for the evaluation of novel treatments for nicotine dependence among cancer patients which address the unique barriers to cessation evident in this population, including: a high level of nicotine dependence, high levels of psychological distress and cognitive impairment, and a protracted relapse timeline. While PHS guidelines recommend acute treatment durations with approved medications for tobacco use, we have shown that extending the duration of treatment beyond the standard treatment duration significantly increases quit rates, reduces the risk for a relapse, and promotes recovery to abstinence following a lapse. Extended duration treatment is particularly efficacious for smokers with high levels of nicotine dependence and cognitive impairment, vs. standard duration treatment, and increases quit rates for smokers with high levels of psychological distress. Varenicline, vs. other medications for smoking, may be particularly effective for cancer patients given the drug's beneficial effects on affect ad cognition. Thus, using a double-blind placebo- controlled design with 374 cancer patients we will: 1) Compare standard varenicline treatment (12-weeks active + 12-weeks placebo) to extended varenicline treatment (24-weeks active) for increasing week 24 and week 52 biochemically-confirmed 7-day point prevalence abstinence~ 2) Assess the effects of extended varenicline therapy on QOL, including varenicline side effects~ and 3) Assess changes in affect and cognitive impairment as mediators of extended varenicline therapy's effect on quit rates. We will also explore potential moderators of the effect of extended varenicline treatment on quit rates (e.g., tumor site and stage, time since diagnosis, treatment history, level of nicotine dependence). This study is significant by addressing a population with high smoking rates, which has been under-studied in the area of nicotine dependence treatment, and is at risk for unique adverse tobacco-related health effects. This study is innovative by evaluating the efficacy of extended vs. standard duration varenicline treatment, which may more effectively address unique barriers to cessation in this population. This will also be the first study to use varenicline blood levels as a measure of adherence. There is widespread agreement that evidence-based treatment programs for nicotine dependence among cancer patients are needed. This study may help guide efforts to implement such programs and help determine the benefits of extended treatment duration for nicotine dependence more broadly. PUBLIC HEALTH RELEVANCE: About 33-50% of cancer patients who smoked before their diagnosis continue to smoke after their diagnosis and continued smoking reduces survival, quality of life, and the effectiveness of their medical treatment. To date, no study has demonstrated an efficacious approach to treating smoking among cancer patients perhaps because these treatments have not adequately addressed barriers to quitting smoking unique to this population, including a high level of nicotine dependence, a high level of psychological distress and cognitive impairment, and a protracted relapse time-line. We have found that extending treatment for nicotine dependence with the nicotine patch from the standard duration to 24-weeks increases quit rates, promotes recovery from a lapse, uniquely helps to mitigate the adverse effects of nicotine dependence and cognitive impairment on attempts to quit smoking, and increases quit rates for smokers with high levels of psychological distress. Varenicline, the most effective treatment currently available for nicotine dependence, reduces negative affect and promotes cognitive function. Thus, this clinical trial will compare standard duration (12- weeks) to extended duration (24-weeks) treatment with varenicline for nicotine dependence among cancer patients. The trial results may serve to guide the development of a treatment model for cancer patients and contribute to a growing literature demonstrating the enhanced efficacy of extended duration treatments for nicotine dependence.